This invention relates to a composition of matter and a method for producing the same, and is particularly related to the compound 6-azido-2-fluoropurine, useful in the synthesis of fludarabine or fludarabine phosphate and related nucleoside pharmacologic agents.
Fludarabine phosphate, also known as 9-.beta.-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate, is a prodrug of the anti-cancer agent, 9-.beta.-D-arabinofuranosyl-2-fluoroadenine. Accordingly, fludarabine phosphate is a chemotherapeutically effective form of the drug and is converted to the parent drug in vivo. U.S. Pat. No. 4,210,745 discloses one method of synthesizing the anti-cancer agent and U.S. Pat. No. 4,357,324 teaches the phosphorylation of said agent to yield fludarabine phosphate. In summary, fludarabine and fludarabine phosphate are commonly made by the following process:
(a) acetylation: 2,6-diaminopurine (also referred to as 2-aminoadenine) in a mixture of pyridine and acetic anhydride is refluxed to yield 2,6-diacetamidopurine, thus protecting the amino groups with acetyl groups;
(b) coupling: 2,3,5-tri-O-benzyl-1-O-p-nitrobenzoyl-D-arabinofuranose is converted to its corresponding chlorosugar 2,3,5-tri-O-benzyl-1-chloro-.alpha.-D-arabinofuranose, which is then coupled with 2,6-diacetamidopurine in ethylene dichloride in the presence of molecular sieves for several days until all of the chlorosugar is consumed, to yield the protected nucleoside 2,6-diacetamido-9-(2,3,5-tri-O-benzyl-.beta.-D-arabinofuranosyl)purine;
(c) deacetylation: the protected nucleoside is refluxed with methanolic sodium methoxide to remove the acetyl groups yielding the nucleoside 2-amino-9-(2,3,5-tri-O-benzyl-.beta.-D-arabinofuranosyl)adenine;
(d) diazotization/fluorination: the protected nucleoside of step (c) undergoes diazotization and fluorination by reaction with sodium nitrite and fluoboric acid in a tetrahydrofuranfluoboric acid (THF-HBF.sub.4) system, to yield 9-(2,3,5-tri-O-benzyl-.beta.-D-arabinofuranosyl)-2-fluoroadenine;
(e) debenzylation: the product from step (d) is treated with boron trichloride to remove the benzyl protecting groups; and lastly
(f) phosphorylation: the product from step (e) is mixed with phosphorous oxychloride in an alkyl phosphate followed by hydrolysis in water, to yield 9-.beta.-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate, or fludarabine phosphate.
One of the disadvantages of this process is that the chlorosugar used in step (b) is very costly. Since the diazotization/fluorination reaction in step (d) has a relatively low yield, much of the chlorosugar is similarly wasted. Therefore, one way to improve this process is by introducing the 2-fluoro group before the coupling step. In this manner, the amount of chlorosugar needed for a given yield, will be reduced. This invention provides one such means of improving the fludarabine synthesis, along with providing a more convergent synthesis of other nucleosides.